7-halo lincomycin carbonate esters

ABSTRACT

THIS INVENTION RELATES TO NOVEL 3-MONO(ALKYL CARBONATE) AND 2,3-BIS(ALKYL CARBONATE) ESTERS OF 7-HALOGENATED LINCOMYCIN COMPOUNDS OF THE FORMULA   2-(R-S-),3-(R4-O-),4-(R3-O-),5-(HO-),6-((1-R2,4-R1-   PYRROLIDIN-2-YL)-CO-NH-CH(-CH(-X)-CH3)-)TETRAHYDROPYRAN   WHEREIN R IS ALKYL OF FROM 1 THROUGH 6 CARBON ATOMS; R1 IS ALKYL OF FROM 1 THROUGH 8 CARBON ATOMS, CYCLOALKYL OF FROM 3 THROUGH 8 CARBON ATOMS, OR ARALKYL OF UP TO 12 CARBON ATOMS; R2 IS HYDROGEN OR ALKYL OF FROM 1 THROUGH 8 CARBON ATOMS; X IS CHLORINE, BROMINE OR IODINE; R3 IS   CNH(2N+1)-OOC-   WHEREIN N IS AN INTEGER FROM 1 THROUGH 20 AND R4 IS R3 OR HYDROGEN; THEIR ACID ADDITION SALTS; AND NOVEL SYNTHESIS PROCESSES. THESE ALKYL CARBONATE ESTERS OF LINCOMYCIN COMPOUNDS HAVE ANTIBIOTIC ACTIVITY. FOR EXAMPLE, THE 3-MONO(ALKYL CARBONATE) ESTERS CAN BE USED TO INHIBIT THE GROWTH OF STAPHYLOCOCCUS AUREUS, STREPTOCOCCUS HEMOLYTICUS AND STREPTOCOCCUS FAECALIS ON MEDIAL AND DENTAL EQUIPMENT CONTAMINATED WITH THESE BACTERIA. THE 2,3-BIS(HEXLY CARBONATE) ESTER OF 7-DEOXY-7(S)-CHLOROLINCOMYCIN IS ADVANTAGEOUS FOR ORAL ADMINISTRATION AS AN ANTIBIOTIC IN THAT IT LACKS THE BITTER TASTE OF THE UNESTERIFIED COMPOUND.

United States Patent O 3,631,021 7-HALO LINCOMYCIN CARBONATE ESTERS Anthony A. Sinkula, Kalamazoo, Mich, assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Apr. 15, 1969, Ser. No. 816,417 Int. Cl. C07c 47/18 US. Cl. 260-210 R 25 Claims ABSTRACT OF THE DISOLOSURE This invention relates to novel 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of 7-halogenated lincomycin compounds of the formula wherein R is alkyl of from 1 through 6 carbon atoms; R is alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, or aralkyl of up to 12 carbon atoms; R is hydrogen or alkyl of from 1 through 8 carbon atoms; X is chlorine, bromine or iodine; R is C Hzn'H OPJ- wherein n is an integer from 1 through and R is R or hydrogen; their acid addition salts; and novel synthesis processes.

These alkyl carbonate esters of lincomycin compounds have antibiotic activity. For example, the 3-mono(alkyl carbonate) esters can be used to inhibit the growth of Staphylococcus aureus, Streptococcus hemolyticus and Streptococcus faecalis on medial and dental equipment contaminated with these bacteria. The 2,3-bis(hexyl carbonate) ester of 7-deoxy-7(S)-chlorolincornycin is ad vantageous for oral administration as an antibiotic in that it lacks the bitter taste of the unesterified compound.

BRIEF SUMMARY OF THE INVENTION The novel 3-mono(alkyl carbonate) and 2,3-bis(alky1 carbonate) esters of 7-halogenated lincomycin compounds of this invention are given by Formula I:

wherein R is alkyl of from 1 through 6 carbon atoms; R is alkyl of from 1 through 8 carbon atoms, or aralkyl of up to 12 carbon atoms, and is located above the plane of the pyrrolidine ring as drawn to give the transconfigura- 3,631 ,ml Patented Dec. 28, 1971 tion with respect to the carbonyl group, or below the ring to give the cis configuration; R is hydrogen or alkyl from 1 through 8 carbon atoms; X is chlorine, bromine or iodine and is situated to the left of the vertical line as drawn to give the 7(R) configuration or to the right to give the 7(S) configuration; R is wherein n is an integer from 1 through 20 are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl, octadecyloxycarbonyl, eicosyloxycarbonyl and isomers of the alkyl moieties thereof.

The novel 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of 7-halogenated lincomycin compounds of Formula I exist either in the nonprotonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization of the free base with suitable acids. Salts of 7-halo-7-deoxylincomycin-3-mono(alkyl carbonates) can be made by neutralizing the free base with the appropriate acid to below about pH 7.0 and advantageously to about pH 2 to pH 6. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic, glueonic, lactobionic, phthalic, tartaric, lauric, stearic, salicyclic, 3-phenylsa1icyclic, S-phenylsalicyclic, 3-methyl gluaric, orthosulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,2- cyclohexanedicarboxylic, 4-cyclohexenecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, azobenzenesulfonic, octadecylsulfuric, picric and like acids.

The novel 3-mono(alky1 carbonate) and 2,3-bis(a1kyl carbonate) esters of 7-ha1ogenated lincomycin compounds are prepared by mixing the appropriate 2,3-dihydroxy compound of Formula H:

I on.

V H H H H OH II wherein R, R R and X are as given for Formula I, dissolved in an amine base of the Formula III:

III

wherein R is selected independently from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and the isomeric forms thereof, with an appropriate alkyl halocarbonate of the Formula IV:

wherein n has the meaning above and Y is fluorine, chlorine. bromine or iodine.

The starting compounds of Formula II are prepared in accordance with the procedures described in U.S. Pat. 3,380,992 and Belgian Pats. 676,154; 676,202 and 705,364. In those instances where the desired 7-halogenated lincomycin 3-mono(alkyl carbonate) or 2,3-bis(alkyl carbonate) compound of Formula I is one in which R is hydrogen, simultaneous undesirable acylation at 1-N atom is prevented by first shielding said l-N atom with a protective group subsequently removable by hydrogenolysis. Suitable such groups are trityl, i.e., triphenylmethyl, diphenyl-(p-methoxyphenyl)-methyl, bis-(p-methoxyphenyl)-phenylmethyl, benzyl, or p-nitrobenzyl and hydrocarbyloxycarbonyl groups. Examples of the latter are tertiarybutoxycarbonyl; benzyloxycarbonyl groups of the forwherein W is hydrogen, allyl, or alkyl of not more than 4 carbon atoms, such as phenyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl, and p-allylphenyloxycarbonyl and the like. After esterification of the 1'-N protected lincomycin compound by the process of this invention, the protective group is replaced by hydrogen by hydrogenolysis (in accordance with the procedure described in U.S. Pat. 3,380,992) to yield the desired 3-mono(alkyl carbonate) or 2,3-bis(alkyl carbonate) ester of the l'-N hydrogen lincomycin compound of Formula I.

The amine bases of Formula III are known in the art and can be prepared by published methods. Typical amine bases that can be used in the process of this invention include 3-ethylpyridine, 4-isopropylpyridine, S-butylpyridine, 3-ethyl-4-methylpyridine, 3,4-diisopropylpyridine, 3- methyl-4-dipropyl-5-propylpyridine, 3,5-dimethy1-4-sec.- butylpyridine, and the like.

The alkyl halocarbonates of Formula IV are well known in the art and a wide variety of them have been prepared by known methods; a considerable number are commercially available. Among the alkyl halocarbonates (IV) that can be employed in the above invention process are methyl chlorocarbonate, ethyl bromocarbonate, propyl iodocarbonate, butyl fluorocarbonate, pentyl bromocarbonate, hexyl iodocarbonate, heptyl fluorocarbonate, undecyl chlorocarbonate, tridecyl bromocarbonate, tetradecyl iodocarbonate, pentadecyl fluorocarbonate, hexadecyl chlorocarbonate, heptadecyl bromocarbonate, octodecyl iodocarbonate, nonadecyl fiuorocarbonate and the like, and the isomeric forms thereof.

The novel 7-halo-7-deoxylincomycin 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of Formula I are prepared by merely mixing the free base or acid addition salt of a Z-hydroxy counterpart (Il) dissolved in an amine base (III), with an appropriate alkyl halocarbonate (IV). Inert solvents can be added, if desired. The reaction can be satisfactorily carried out between about 50 C. and +50 C., with heating of the reaction mixture being unnecessary. The nature of the end product, whether 3-mono(a1kyl carbonate) ester or 2,3-bis(alkyl carbonate) ester is established by the molar ratio of alkylhalocarbonate of Formula IV to 2,3-hydroxy-7-halogenated lincomycin compound used. When this ratio is about 2 to about 1, the reaction product is wholly or primarily the 3-mono(alkyl carbonate) ester, whereas when the ratio is about 5 to about 1, the reaction product is wholly or primarily the 2,3-bis(alkyl carbonate) ester. Monoesterification of the 3-hydroxyl group to the essential exclusion of other hydroxyl groups of the 7-halogenated lincomycin compound under the conditions stated above would be unexpected because (1) a considerable excess of halo alkylcarbonate above that required for monoesterification is used, and reaction to yield a variety of polyesters would be expected; and (2) the 3-hydroxyl group is only one of several secondary hydroxyl groups, including the 2-, 3- and 4-hydroxyl groups, so that selectivity toward 3-monoesterification would not be anticipated. Diesterification of the 2- and 3-hydroxyl groups to the essential exclusion of other hydroxyl groups under the conditions stated above is also unexpected because (1) a considerable excess of halo alkylcarbonate above that required for di-esterification is used, and further reaction to yield a tri(alkyl carbonate) ester would be expected; and (2) esterification is restricted selectively to form the 2,3-bis(alkyl carbonate), whereas one should expect that the 4-hydroxyl group, which is also a secondary hydroxyl group, should also be esterified, so that, among any bis(alkyl carbonates) esters formed, considerable yields of 2,4- and 3,4-bis(alkyl carbonate) esters should be produced. Instead, essentially only the 2,3-bis (alkyl carbonate) ester is actually produced in the operation of this invention.

The time required for the completion of the 3-monoesterification or 2,3-diesterification reaction depends upon such factors as the reaction temperature, the particular reactants employed, the relative amount of reactants, thoroughness of mixing, and the like. Therefore, it will be understood that optimum reaction time will vary for each set of reaction conditions. Ordinarily, reaction times ranging from about half an hour to about 48 hours are suitable. If desired, for example for purposes of time economy, the course of the reaction may be monitored by sampling and examining the reaction mixture by methods common to the art, for example by the use of thin-layer chromatography, during the reaction.

After completion of the reaction between the compounds of Formulas II and IV, the desired product of Formula I is isolated from the reaction mixture in either its free base or acid addition salt form. Isolation of the product is carried out by conventional procedures such as filtration, solvent evaporation, solvent extraction; chromatography or crystallization; or a combination of these methods. The desired product so obtained can be purified, e.g., by crystallization from a solvent or suitable mixture of solvents. When the product is in the free base form, it can be converted to an acid addition salt by neutralization with an acid, e.g., any of those given above; when in the acid addition salt form it can be transformed to the free base, e.g., by treatment with a strongly basic anion exchange resin.

To facilitate an understanding of the molecular structure and nomenclature employed herein to identify the novel compounds of Formula I, their ultimate plecusor, lincomycin, has its structural formula and chemical name provided below, for comparison. Lincomycin, also named methyl 6,8 dideoxy-6-(trans-l-methyl-4-propyl-L-2-pyrrolidenecarboxamido) l thio D-erythro-a-D-galactooctopyranoside, is obtained as an elaboration product of a lincomycin-producing actinomycete in accordance with US. Pat. 3,086,912; it has the following structural formula CHgCHgCHg 1 /N on, H H HO---- l H H0 H H H H OH H n I son H on DETAILED DESCRIPTION It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described herein, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

EXAMPLE 1 7 (S -chl0r0-7-de0xylincomycin-3- pcntyl carbonate) hydrochloride A solution of 9.63 g. (0.02 mole) of 7(S)-chloro-7- deoxylincomycin hydrochloride [also named methyl 7- chloro-6,7,8-trideoxy 6-(trans 1 methyl-4-propyl-L-2- pyrrolidinecarboxamido) 1 thio-L-threo-a-D-galactooctopyranoside hydrochloride] (prepared as in Belgian Pat. 676,154 and page 731 of Antimicrobial Agents and Chemotherapy1966, American Society for Microbiology, 1967, Ann Arbor, Mich.) in 100 ml. of pyridine is cooled to about 30 C., and 6.02 g. (0.04 mole) of n-amyl chlorocarbonate added dropwise. This solution is warmed to room temperature, stirred for about 1 hour, then cooled to about 30 C., 2 g. of n-amyl chlorocarbonate added, and stirred for about 2 hours. The pyridine solution is poured into 1 l. of ice water acidified to pH 2 with concentrated hydrochloric acid. The resulting aqueous suspension is extracted with two 250 ml. portions of chloroform, the chloroform extracts combined, and dried over anhydrous magnesium sulfate. The chloroform is removed under vacuum at 38 C. The resulting white precipitate is shaken with 750 ml. of anhydrous ether, collected by filtration, air-dried for about one hour, then dried for about 16 hours under vacuum at 45 C. The crude product, 6.75 g. of 7(S)-chloro-7- deoxylincomycin-3-(pentyl carbonate) hydrochloride, is equilibrated between 700' ml. of ether and 460 ml. of aqueous buffer of pH 2.2 in a 2 1. separatory funnel. After vigorous shaking of the funnel, the ether layer is removed and discarded; the aqueous layer is extracted again with 800 m1. of ether and the ether extract removed and discarded. The aqueous layer is next extracted with 780 ml. of chloroform (in two portions), and the chloroform extracts pooled, dried with anhydrous sodium sulfate, evaporated to dryness under vacuum at about 50 C. [he resulting residual light yellow oil is taken up in 80 ml. of chloroform, which is then saturated with anhydrous hydrogen chloride, and again reduced to dryness under vacuum at about 50 C., to give 2.65 g. of white solid 7 (S)-chlor0-7-deoxylincornycin-3-(pentyl carbonate) hydrochoride.

Analysis.-Calcd. for C H N O SCl (percent): C, 50.08; H, 7.71; N, 4.87; Cl, 12.32. Found (corrected for 1.8% H 0 (percent)): C, 48.24; H, 7. 60; N, 4.61; CI, 13.17.

7(S)-chloro-7-deoxy1incomycin 3 (pentyl carbonate) hydrochloride has antibacterial activity against Staphylococcus aureus equivalent to 180 micrograms of lincomycin per mg. Its relative molar CD is 0.37 times that of lin- 6 comycin when administered subcutaneously to mice infected with this organism.

7(S) chloro-7-deoxylincomycin-3-(pentyl carbonate) hydrochloride is converted to its free base, 7(S)-chloro- 7-deoxylincomycin-3-(pentyl carbonate), by treatment with a strongly basic anion exchange resin. [Suitable anion exchange resins for this purpose are obtained by chlormethylating by the procedure given on pages 88 and 97 of Kunin, Ion Exchange Resins, 2nd edition (1958), John Wiley and Sons, Inc., polystyrene crosslinked, if desired, with divinylbenzene prepared by the procedure given on page 84 of Kunin, supra, and quaternizing with trimethylamine, or dimethylethanolamine by the procedure given on page 97 of Kunin, supra. Anion exchange resins of this type are marketed under the trade names Dowex 2, DoWex 20, Amberlite IRA-400, Duolite A- 102, and Permutit 8-1.] The 7(S)-chloro-7-deoxylincomycin-3-(pentyl carbonate) is converted to other salts by contacting with other acids as previously disclosed.

Following the procedure of Example 1 but substituting 7(S) chloro-7-deoxylincomycin for its hydrochloride, yields 7(S)-chloro-7-deoxylincomycin-3-(pentyl carbonate).

Following the procedure of Example 1 but substituting 7(R)-chloro-7-deoxylincomycin or its acid addition salts as the starting material, yields 7(R)-chloro-7-deoxylincomycin-3-(pentyl carbonate) or its acid addition salt.

EXAMPLE 2 Further 3-m0n0alkylcarb0nates Following the procedure of Example 1, especially as pertains to ratio of moles of alkyl halocarbonate to moles of starting 7-halogenated lincomycin compound or 1- protected-7-halogenated lincomycin compound but substituting for n-amyl chlorocarbonate another alkyl halocarbonate such as methyl bromocarbonate, ethyl fluorocarbonate, propyl iodocarbonate,

butyl chlorocarbonate, hexyl bromocarbonate, octyl fluorocarbonate,

(7) decyl iodocarbonate,

( 8) dodecyl chlorocarbonate, (9) tetradecyl bromocarbonate, (10) hexadecyl fluorocarbonate, (11 hexadecyl iodocarbonate, (12) octadecyl chlorocarbonate, (13) nonadecyl bromocarbonate, (14) eicosyl chlorocarbonate yields respectively,

Following the procedure of the immediately preceding paragraph but substituting for pyridine (employed in Example 1), another amine base such as 3-methylpyridine, 4-propylidine, S-butylpyridine, 3-methyl-4-ethylpyridine, 3,4-dibutylpyridine, 3-ethyl-4-isopropylpyridine, 3-propyl- 5 4-isobutylpyridine, 3-ethyl-5-propylpyridine, 3,5-dimethylpyridine, 3-isopropyl-5-sec. butylpyridine, 3,4,5-trimethylpyridine, 3,4-dibutyl-5-propylpyridine, 3-ethyl-4-propyl-5- butylpyridine, 3,5 diethyl 4 methylpyridine, etc., also H H s a f l o-NH- yields the compounds prepared in the aforesaid paragraph. 10 HO /5 H EXAMPLE 3 4 CR3 H 1 7 (S )-chl0r0-7-de0xylincomycin-2,3-bis(hexyl carbonate) H SR hydrochloride H OH 7(S)-chloro-7-deoxylincomycin hydrochloride monohydrate (9.63 g., 0.02 mole) is dissolved in 150 ml. of AR pyridine and cooled to 30 C. n-Hexyl chlorocarbonate (Eastman White Label) is added dropwise with good stirring. The reaction mixture is slowly warmed to room temperature and stirred for one hour. The solution is recooled, 10 g. more of n-hexyl chlorocarbonate added, and warmed to room temperature. The mixture is poured into 1500 ml. of ice-water acidified to pH 2 with concentrated hydrochloric acid, stirred thoroughly, and extracted with two 750 ml. portions of ether. The ether layer is dried with anhydrous magnesium sulfate and concentrated on a stream bath. The resulting precipitate (syrup) is vacuum-dried thoroughly and shaken vigorously with 500 ml. of anhydrous ether. The resulting tan precipitate is resuspended in 500 ml. of ether and filtered. The resulting white crystalline 7(S)-chloro-7-deoxylincomycin-2,3-bis(hexyl carbonate) hydrochloride is dried in a vacuum oven at 50 C. for three days. Yield 8 gm. (55.7%

Analysis.-Calcd. for S H N SO' Cl (percent: C, 53,55; H, 8.14; N, 3.90; CI, 9.88. Eq. wt., 717.80. Found (corrected for H 0) (percent): C, 53.47; H, 8.28; N, 4.14; S, Cl, 9.89. Eq. wt., 714.

EXAMPLE 4 Further 2,3-bis(alkyl carbonates) Following the procedure of Example 3, especially as pertains to the ratio of moles of alkyl halocarbonate to moles of starting 7-halogenated lincomycin compound or 1-protected-7-halongenated lincomycin compound, but substituting the 7-halogenated lincomycin starting compounds and alkyl halocarbonates given in Example 2, there are afforded the corresponding 2,3-bis(alkyl carbonate) esters of the 7-halogenated lincomycin compounds. Treating representative 7-halogenated lincomycin compounds with representative alkyl halocarbonates, for example:

wherein R is alkyl of from 1 through 6 carbon atoms, R is selected from the group consisting of alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, and aralkyl of up to 12 carbon atoms; R is selected from the group consisting of hydrogen and alkyl of from 1 through 8 carbon atoms; X is selected from the group consisting of chlorine, bromine and iodine; and R is o n 2n+l wherein n is an integer from 1 through and the acid addition salts thereof.

2. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7(S)-chloro, and R is as defined in claim 1; and the acid addition salts thereof.

3. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7(S)-chl0ro and R is pentyloxycarbonyl; and acid addition salts thereof.

4. A hydrochloric acid addition salt of the compound of claim 3.

5. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7(S)-chloro, and R is hexadecyloxycarbonyl; and the acid addition salts thereof.

6. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chlor0, and R is as defined in claim 1; and acid addition salts thereof.

7. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chloro, and R is hexyloxycarbonyl; and acid addition salts thereof.

8. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chloro, and R is hexadecyloxycarbonyl; and the acid addition salts thereof.

9. A compound of claim 1 in which R is methyl, R is trans-n-pentyl, R is hydrogen, X is 7(S)-chloro, and R is as defined in claim 1; and the acid addition salts thereof.

10. A compound of claim 1 in which R is methyl, R is trans-n-pentyl, R is hydrogen, X is 7(S)-chloro, and R is hexyloxycarbonyl; and the acid addition salts thereof.

11. A compound of claim 10 in which the acid addition pentyl-7(S)-chloro-7-deoxylincomycin and decyl iodocarbonate,

(3) S-desmethyl-S-ethyl 7(S) chloro 7 deoxylincomycin citrate and hexadecyl chlorocarbonate,

(4) 4'-despropyl-4-n pentyl 1' carbobenzoxy 7(S)- chloro-7-deoxylincomycin hydrochloride and hexadecyl fiuorocarbonate, etc.

salt is the hydrochloride.

12. A compound of claim 1 in which R is methyl, R is trans-n-propyl, R is ethyl, X is 7(S)-chloro, and R is hexadecyloxycarbonyl; and the acid addition salts thereof.

13. A compound of the formula:

yields, respectively,

(1) 7 (S)-bromo- 7 deoxylincomycin 2,3 bis(propyl carbonate) 5 g PX (2) 1-desmethyl-l-carbobenzoxy 4' despropyl 4 H 4 n-pentyl-7 (S)-chloro-7-deoxylincomycin-2,3 bis(dexyl g carbonate) R; H H0 5 H (3) S-desmethyl-S-ethyl-7(S)-ch1oro 7 deoxylincomy- 4 0B3 11 1 cin-2,3-bis(hexadecyl carbonate) citrate, H F SR 4) 4'-despropyl-4-n-pentyl 1' carbonbenzoxy 7(S)- chloro-7-deoxy1incomycin-2,3-bis(hexadecyl carbonate) H 0R4 hydrochloride, etc.

wherein R is alkyl of from 1 through 6 carbon atoms;

1 1 R is selected from the group consisting of alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, and aralkyl of up to 12 carbon atoms; R is selected from the group consisting of hydrogen and alkyl of from 1 through 8 carbon atoms; X is selected from the group consisting of chlorine, bromine and iodine; R and R are 0 0 H211 l'-0 wherein n is an integer from 1 through 20; and the acid addition salts thereof.

14. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7 (S)-chloro, and R and R are as defined in claim 13; and the acid addition salts thereof.

15. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7(S)-chloro, and R and R are hexyloxycarbonyl; and the acid addition salts thereof.

16. A hydrochloric acid addition salt of the compound of claim 15.

17. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is methyl, X is 7(S)-chloro, and R and R are hexadecyloxycarbonyl; and the acid addition salts thereof.

18. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chloro, and R and R are as defined in claim 13; and the acid addition salts thereof.

19. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chl0ro, and R and R are hexyloxycarbonyl; and the acid addition salts thereof.

20. A compound of claim 19 in which the acid addition salt is the hydrochloride.

21. A compound of claim 13 in which R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chloro, and R and R are hexadecyloxycarbonyl; and the acid addition salts thereof.

22. A compound of claim 13 in which R is methyl, R is trans-n-pentyl, R is hydrogen, X is 7(S)-chloro, and R and R are defined as in claim 13; and the acid addition salts thereof.

23. A compound of claim 13 in which R is methyl, R is trans-n-pentyl, R is hydrogen, X is 7 (S)-chloro, and R and R are hexyloxycarbonyl; and the acid addition salts thereof.

24. A compound of claim 23 in which the acid addition salt is a hydrochloride.

25. A compound of claim 13 in which R is methyl, R is trans-n-pentyl, R is hydrogen, X is 7(S)-chloro, and R and R are hexadecyloxycarbonyl; and the acid add tion salts thereof.

References Cited 

